Nitazoxanide versus metronidazole for Clostridium difficile-associated colitis.

To the Editor—Reports of increased incidence and severity of Clostridium difficile–associated colitis have stimulated interest in the search for additional treatment options for this clinical problem. Musher et al. [1] recently reported the results of a noninferiority study that compared metronidazole with nitazoxanide for the treatment of C. difficile colitis. The authors concluded that “nitazoxanide is as effective as metronidazole” (p. 425) for this infection. Scrutiny of some aspects of the study design and analysis calls this conclusion into question. Notably, there was an unexplained exclusion of a significant number of the initially enrolled patients. The investigators compared the baseline characteristics and severity of illness in an “intent-to-treat” population; however, 32 enrolled and randomized patients were excluded before any efficacy analysis. Therefore, this was not an intent-to-treat analysis. The 110 subjects included in the primary efficacy analysis may have been very different than the initial 142 enrolled patients, and some effects of randomization were possibly lost. In addition, it is not revealed specifically what adverse events occurred among the excluded patients, and the cause of death was not revealed for any patient. The reader is told that 9.1% of the original 142 patients died, “indicating the severity of underlying disease(s) and/or the colitis” [1, p. 424]. This implies that some deaths were due to complications of C. difficile– associated colitis. This point should have been clarified. If adverse events or deaths were even peripherally related to colitis, the exclusion of these patients brings the study results into question. There were other concerns regarding this study. (1) The investigators did not analyze the minimum number of subjects required in each group and, therefore, did not achieve adequate statistical power to reject the null hypothesis. (2) When using an active control with no placeboonly group, one should employ a doubledummy design to maintain true doubleblinding. Metronidazole and nitazoxanide do not resemble one another and have different dosing schedules. Although the randomization was blinded, it appears that the study drugs were not administered in a strictly double-blind fashion. (3) The reader is not told the proportion of subjects in each group who continued to receive the original offending antibiotic(s) that presumably led to C. difficile–associated colitis. With such a small study, one cannot rely on randomization to eliminate the effects of thispotential confounder. On the basis of in vitro susceptibility data, a hamster model of disease [2], and the clinical trial by Musher et al. [1], it appears that nitazoxanide does have some efficacy in treating C. difficile–associated colitis. However, one should not conclude that it is as effective as metronidazole on the basis of this study. If noninferiority to metronidazole had been shown appropriately, the significantly higher cost of nitazoxanide makes this drug difficult to recommend as an alternative treatment. The role of nitazoxanide in current clinical practice remains undefined.